Is EGFLAM p.Trp229Arg (c.685T>C) pathogenic?

EGFLAM p.Trp229Arg (c.685T>C) is classified Benign in EGFLAM (ClinVar, Multiple submitters, 2 submitters; last evaluated 2019-01-09). AlphaMissense: likely benign (0.0706); Common (popmax 40.9%, afr) — too common for a highly-penetrant pathogenic allele.

What do computational predictors say about EGFLAM p.Trp229Arg (c.685T>C)?

AlphaMissense predicts likely benign (score 0.0706) — an in-silico prediction, not a clinical call.

EGFLAM p.Trp229Arg

Q: How common is EGFLAM p.Trp229Arg (c.685T>C) in the general population?

EGFLAM p.Trp229Arg (c.685T>C) is common (popmax 40.9%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.685T>C · rs1465567 · VCV1235521

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0706 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 40.9%, afr) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0706	likely benign
REVEL	0.028	moderately benign-leaning
SaProt	LLR -2.24	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.16	GERP -3.4
Regional constraint	o/e 0.98	unconstrained · MANE · 205 kb · p 0.46 · regional, not allelic
Overall
CADD	7.536	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 40.9% African / African-American · 30,668/74,956 alleles

Filtering AF 40.5% ClinGen BA1/BS1 input FAF95, joint · FAF99 40.4%

Overall 20.5% 330,831/1,613,854 alleles · common

Ancestry group	Frequency	1 in
African / African-Americangrpmax	40.9%	2
Middle Eastern	24.1%	4
Ashkenazi Jewishnot grpmax-eligible	22%	5
East Asian	21.5%	5
South Asian	21.1%	5
Remaining individualsnot grpmax-eligible	21%	5
European (non-Finnish)	19.3%	5
Finnishnot grpmax-eligible	18.4%	5
Admixed American	16.9%	6
Amishnot grpmax-eligible	13%	8

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: EGFLAM
Protein: p.Trp229Arg
Coding: c.685T>C
MANE Select: NM_152403
dbSNP: rs1465567
Type: single nucleotide variant
Location: chr5:38370435 (GRCh38)
Gene constraint: LOEUF 0.83 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 80.81 · 3 PDB
Residue 229: a UniProt-annotated variant site (in); the fibronectin type-iii 2 domain; an α-helix

Full EGFLAM gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

EGFLAM p.Asn913= Benign ★★ same type
EGFLAM c.2465-2611T>C Uncertain significance ★ ⚠ same type
EGFLAM p.Ala115Val Uncertain significance ★ ⚠ same type
EGFLAM p.Ala143Pro Uncertain significance ★ ⚠ same type
EGFLAM p.Ala314Thr Uncertain significance ★ ⚠ same type
EGFLAM p.Ala45Thr Uncertain significance ★ ⚠ same type
EGFLAM p.Ala515Thr Uncertain significance ★ ⚠ same type
EGFLAM p.Ala518Thr Uncertain significance ★ ⚠ same type

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/egflam-p-trp229arg (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown